Abstract
Developments of many renal diseases are substantially influenced by epigenetic modifications of numerous genes, mainly mediated by DNA methylations, histone modifications, and microRNA interference; however, not all gene modifications causally affect the disease onset or progression. Klotho is a critical gene whose repressions in various pathological conditions reportedly involve epigenetic regulatory mechanisms. Klotho is almost unexceptionally repressed early after acute or chronic renal injuries and its levels inversely correlated with the disease progression and severity. Moreover, the strategies of Klotho derepression via epigenetic modulations beneficially change the pathological courses both in vitro and in vivo. Hence, Klotho is not only considered a biomarker of the renal disease but also a potential or even an ideal target of therapeutic epigenetic intervention. Here, we summarize and discuss studies that investigate the Klotho repression and intervention in renal diseases from an epigenetic point of view. These information might shed new sights into the effective therapeutic strategies to prevent and treat various renal disorders.
Similar content being viewed by others
References
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E et al (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51
Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H et al (2005) Suppression of aging in mice by the hormone Klotho. Science 309:1829–1833
Ito S, Fujimori T, Hayashizaki Y, Nabeshima Y (2002) Identification of a novel mouse membrane-bound family 1 glycosidase-like protein, which carries an atypical active site structure. Biochim Biophys Acta 1576:341–345
Ito S, Kinoshita S, Shiraishi N, Nakagawa S, Sekine S, Fujimori T, Nabeshima YI (2000) Molecular cloning and expression analyses of mouse betaklotho, which encodes a novel Klotho family protein. Mech Dev 98:115–119
Li SA, Watanabe M, Yamada H, Nagai A, Kinuta M, Takei K (2004) Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct 29:91–99
Xu Y, Sun Z (2015) Molecular basis of Klotho: from gene to function in aging. Endocr Rev 36:174–193
Lu X, Hu MC (2017) Klotho/FGF23 axis in chronic kidney disease and cardiovascular disease. Kidney Dis (Basel) 3:15–23
Erben RG (2016) Update on FGF23 and Klotho signaling. Mol Cell Endocrinol 432:56–65
Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, Fujimori T, Nabeshima Y (2004) Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 565:143–147
Akimoto T, Yoshizawa H, Watanabe Y, Numata A, Yamazaki T, Takeshima E, Iwazu K, Komada T, Otani N, Morishita Y et al (2012) Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease. BMC Nephrol 13:155
Lim K, Groen A, Molostvov G, Lu T, Lilley KS, Snead D, James S, Wilkinson IB, Ting S, Hsiao LL et al (2015) alpha-Klotho expression in human tissues. J Clin Endocrinol Metab 100:E1308–E1318
Cha SK, Ortega B, Kurosu H, Rosenblatt KP, Kuro OM, Huang CL (2008) Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci U S A 105:9805–9810
Hu MC, Kuro-o M, Moe OW (2012) Secreted klotho and chronic kidney disease. Adv Exp Med Biol 728:126–157
Hu MC, Kuro-o M, Moe OW (2013) Klotho and chronic kidney disease. Contrib Nephrol 180:47–63
Neyra JA, Hu MC (2017) Potential application of klotho in human chronic kidney disease. Bone 100:41–49
Christov M, Neyra JA, Gupta S, Leaf DE (2019) Fibroblast growth factor 23 and Klotho in AKI. Semin Nephrol 39:57–75
Moreno JA, Izquierdo MC, Sanchez-Nino MD, Suarez-Alvarez B, Lopez-Larrea C, Jakubowski A, Blanco J, Ramirez R, Selgas R, Ruiz-Ortega M et al (2011) The inflammatory cytokines TWEAK and TNFalpha reduce renal klotho expression through NFkappaB. J Am Soc Nephrol 22:1315–1325
Azuma M, Koyama D, Kikuchi J, Yoshizawa H, Thasinas D, Shiizaki K, Kuro-o M, Furukawa Y, Kusano E (2012) Promoter methylation confers kidney-specific expression of the Klotho gene. FASEB J 26:4264–4274
Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M (2012) Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov 11:384–400
Shiels PG, McGuinness D, Eriksson M, Kooman JP, Stenvinkel P (2017) The role of epigenetics in renal ageing. Nat Rev Nephrol 13:471–482
Pal S, Tyler JK (2016) Epigenetics and aging. Sci Adv 2:e1600584. https://doi.org/10.1126/sciadv.1600584
Wuttke M, Kottgen A (2016) Insights into kidney diseases from genome-wide association studies. Nat Rev Nephrol 12:549–562
Smyth LJ, McKay GJ, Maxwell AP, McKnight AJ (2014) DNA hypermethylation and DNA hypomethylation is present at different loci in chronic kidney disease. Epigenetics 9:366–376
Wanner N, Bechtel-Walz W (2017) Epigenetics of kidney disease. Cell Tissue Res 369:75–92
Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150:12–27
Horvath S, Raj K (2018) DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 19:371–384
Moore LD, Le T, Fan G (2013) DNA methylation and its basic function. Neuropsychopharmacology 38:23–38
Hu L, Li Z, Cheng J, Rao Q, Gong W, Liu M, Shi YG, Zhu J, Wang P, Xu Y (2013) Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation. Cell 155:1545–1555
Bochtler M, Kolano A, Xu GL (2017) DNA demethylation pathways: additional players and regulators. Bioessays 39:1–13
Melamed P, Yosefzon Y, David C, Tsukerman A, Pnueli L (2018) Tet enzymes, variants, and differential effects on function. Front Cell Dev Biol 6:22
Koch A, Joosten SC, Feng Z, de Ruijter TC, Draht MX, Melotte V, Smits KM, Veeck J, Herman JG, Van Neste L et al (2018) Analysis of DNA methylation in cancer: location revisited. Nat Rev Clin Oncol 15:459–466
Rubinek T, Shulman M, Israeli S, Bose S, Avraham A, Zundelevich A, Evron E, Gal-Yam EN, Kaufman B, Wolf I (2012) Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast Cancer Res Treat 133:649–657
Xie B, Zhou J, Yuan L, Ren F, Liu DC, Li Q, Shu G (2013) Epigenetic silencing of Klotho expression correlates with poor prognosis of human hepatocellular carcinoma. Hum Pathol 44:795–801
Lee J, Jeong DJ, Kim J, Lee S, Park JH, Chang B, Jung SI, Yi L, Han Y, Yang Y et al (2010) The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma. Mol Cancer 9:109
King GD, Rosene DL, Abraham CR (2012) Promoter methylation and age-related downregulation of Klotho in rhesus monkey. Age (Dordr) 34:1405–1419
Li Y, Chen F, Wei A, Bi F, Zhu X, Yin S, Lin W, Cao W (2019) Klotho recovery by genistein via promoter histone acetylation and DNA demethylation mitigates renal fibrosis in mice. J Mol Med (Berl) 97:541–552
Yin S, Zhang Q, Yang J, Lin W, Li Y, Chen F, Cao W (2017, 1864) TGFbeta-incurred epigenetic aberrations of miRNA and DNA methyltransferase suppress Klotho and potentiate renal fibrosis. Biochim Biophys Acta, Mol Cell Res:1207–1216. https://doi.org/10.1016/j.bbamcr.2017.03.002
Zhang Q, Liu L, Lin W, Yin S, Duan A, Liu Z, Cao W (2017) Rhein reverses Klotho repression via promoter demethylation and protects against kidney and bone injuries in mice with chronic kidney disease. Kidney Int 91:144–156
Hu MC, Shi M, Gillings N, Flores B, Takahashi M, Kuro OM, Moe OW (2017) Recombinant alpha-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int 91:1104–1114
Yu D, Zhang L, Yu G, Nong C, Lei M, Tang J, Chen Q, Cai J, Chen S, Wei Y et al (2019) Association of liver and kidney functions with Klotho gene methylation in a population environment exposed to cadmium in China. Int J Environ Health Res 30:38–48
Hu MC, Shi M, Zhang J, Quinones H, Kuro-o M, Moe OW (2010) Klotho deficiency is an early biomarker of renal ischemia-reperfusion injury and its replacement is protective. Kidney Int 78:1240–1251
Seo MY, Yang J, Lee JY, Kim K, Kim SC, Chang H, Won NH, Kim MG, Jo SK, Cho W et al (2015) Renal Klotho expression in patients with acute kidney injury is associated with the severity of the injury. Korean J Intern Med 30:489–495
Kim AJ, Ro H, Kim H, Chang JH, Lee HH, Chung W, Jung JY (2016) Klotho and S100A8/A9 as discriminative markers between pre-renal and intrinsic acute kidney injury. PLoS One 11:e0147255. https://doi.org/10.1371/journal.pone.0147255
Chen J, Zhang H, Hu J, Gu Y, Shen Z, Xu L, Jia X, Zhang X, Ding X (2017) Hydrogen-rich saline alleviates kidney fibrosis following AKI and retains Klotho expression. Front Pharmacol 8:499
Bi F, Chen F, Li Y, Wei A, Cao W (2018) Klotho preservation by Rhein promotes toll-like receptor 4 proteolysis and attenuates lipopolysaccharide-induced acute kidney injury. J Mol Med (Berl) 96:915–927
Zhang Q, Yin S, Liu L, Liu Z, Cao W (2016) Rhein reversal of DNA hypermethylation-associated Klotho suppression ameliorates renal fibrosis in mice. Sci Rep 6:34597
Tsai KD, Lee WX, Chen W, Chen BY, Chen KL, Hsiao TC, Wang SH, Lee YJ, Liang SY, Shieh JC et al (2018) Upregulation of PRMT6 by LPS suppresses Klotho expression through interaction with NF-kappaB in glomerular mesangial cells. J Cell Biochem 119:3404–3416
Tikoo K, Ali IY, Gupta J, Gupta C (2009) 5-Azacytidine prevents cisplatin induced nephrotoxicity and potentiates anticancer activity of cisplatin by involving inhibition of metallothionein, pAKT and DNMT1 expression in chemical induced cancer rats. Toxicol Lett 191:158–166
Guo C, Pei L, Xiao X, Wei Q, Chen JK, Ding HF, Huang S, Fan G, Shi H, Dong Z (2017) DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8. Kidney Int 92:1194–1205
Zou D, Wu W, He Y, Ma S, Gao J (2018) The role of klotho in chronic kidney disease. BMC Nephrol 19:285
Chen J, Zhang X, Zhang H, Lin J, Zhang C, Wu Q, Ding X (2013) Elevated Klotho promoter methylation is associated with severity of chronic kidney disease. PLoS One 8:e79856. https://doi.org/10.1371/journal.pone.0079856
Young GH, Wu VC (2012) KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int 81:611–612
Sun CY, Chang SC, Wu MS (2012) Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney Int 81:640–650
Chen J, Zhang X, Zhang H, Liu T, Zhang H, Teng J, Ji J, Ding X (2016) Indoxyl sulfate enhance the hypermethylation of Klotho and promote the process of vascular calcification in chronic kidney disease. Int J Biol Sci 12:1236–1246
Zhang C, Liang Y, Lei L, Zhu G, Chen X, Jin T, Wu Q (2013) Hypermethylations of RASAL1 and KLOTHO is associated with renal dysfunction in a Chinese population environmentally exposed to cadmium. Toxicol Appl Pharmacol 271:78–85
Ruiz-Andres O, Sanchez-Nino MD, Moreno JA, Ruiz-Ortega M, Ramos AM, Sanz AB, Ortiz A (2016) Downregulation of kidney protective factors by inflammation: role of transcription factors and epigenetic mechanisms. Am J Physiol Ren Physiol 311:F1329–F1340
Larkin BP, Glastras SJ, Chen H, Pollock CA, Saad S (2018) DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease. FASEB J 32:5215–5226
Dwivedi RS, Herman JG, McCaffrey TA, Raj DS (2011) Beyond genetics: epigenetic code in chronic kidney disease. Kidney Int 79:23–32
Liu L, Liu Y, Zhang Y, Bi X, Nie L, Liu C, Xiong J, He T, Xu X, Yu Y et al (2018) High phosphate-induced downregulation of PPARgamma contributes to CKD-associated vascular calcification. J Mol Cell Cardiol 114:264–275
Jung D, Xu Y, Sun Z (2017) Induction of anti-aging gene klotho with a small chemical compound that demethylates CpG islands. Oncotarget 8:46745–46755
Chen K, Sun Z (2018) Activation of DNA demethylases attenuates aging-associated arterial stiffening and hypertension. Aging Cell 17:e12762. https://doi.org/10.1111/acel.12762
Nastase MV, Zeng-Brouwers J, Wygrecka M, Schaefer L (2018) Targeting renal fibrosis: mechanisms and drug delivery systems. Adv Drug Deliv Rev 129:295–307
Morgado-Pascual JL, Marchant V, Rodrigues-Diez R, Dolade N, Suarez-Alvarez B, Kerr B, Valdivielso JM, Ruiz-Ortega M, Rayego-Mateos S (2018) Epigenetic modification mechanisms involved in inflammation and fibrosis in renal pathology. Mediat Inflamm 2018:2931049
Lindberg K, Amin R, Moe OW, Hu M-C, Erben RG, Östman Wernerson A, Lanske B, Olauson H, Larsson TE (2014) The kidney is the principal organ mediating klotho effects. J Am Soc Nephrol 25:2169–2175
Doi S, Zou Y, Togao O, Pastor JV, John GB, Wang L, Shiizaki K, Gotschall R, Schiavi S, Yorioka N et al (2011) Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem 286:8655–8665
Zhou L, Li Y, Zhou D, Tan RJ, Liu Y (2013) Loss of Klotho contributes to kidney injury by derepression of Wnt/beta-catenin signaling. J Am Soc Nephrol 24:771–785
Satoh M, Nagasu H, Morita Y, Yamaguchi TP, Kanwar YS, Kashihara N (2012) Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling. Am J Physiol Ren Physiol 303:F1641–F1651
Guan X, Nie L, He T, Yang K, Xiao T, Wang S, Huang Y, Zhang J, Wang J, Sharma K et al (2014) Klotho suppresses renal tubulo-interstitial fibrosis by controlling basic fibroblast growth factor-2 signalling. J Pathol 234:560–572
Yamamoto M, Clark JD, Pastor JV, Gurnani P, Nandi A, Kurosu H, Miyoshi M, Ogawa Y, Castrillon DH, Rosenblatt KP et al (2005) Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem 280:38029–38034
Ortiz Arduan A (2012) Aging and inflammation: Klotho, diet and the kidney connection. An R Acad Nac Med (Madr) 129:231–242 discussion 242-234
Hu Y, Mou L, Yang F, Tu H, Lin W (2016) Curcumin attenuates cyclosporine A induced renal fibrosis by inhibiting hypermethylation of the klotho promoter. Mol Med Rep 14:3229–3236
Xu X, Tan X, Tampe B, Wilhelmi T, Hulshoff MS, Saito S, Moser T, Kalluri R, Hasenfuss G, Zeisberg EM et al (2018) High-fidelity CRISPR/Cas9- based gene-specific hydroxymethylation rescues gene expression and attenuates renal fibrosis. Nat Commun 9:3509
Gu Y, Chen J, Zhang H, Shen Z, Liu H, Lv S, Yu X, Zhang D, Ding X, Zhang X (2020) Hydrogen sulfide attenuates renal fibrosis by inducing TET-dependent DNA demethylation on Klotho promoter. FASEB J 34:11474–11487
Thomas MC, Brownlee M, Susztak K, Sharma K, Jandeleit-Dahm KA, Zoungas S, Rossing P, Groop PH, Cooper ME (2015) Diabetic kidney disease. Nat Rev Dis Primers 1:15018
Kim SS, Song SH, Kim IJ, Lee EY, Lee SM, Chung CH, Kwak IS, Lee EK, Kim YK (2016) Decreased plasma alpha-Klotho predict progression of nephropathy with type 2 diabetic patients. J Diabetes Complicat 30:887–892
Wu C, Ma X, Zhou Y, Liu Y, Shao Y, Wang Q (2019) Klotho restraining Egr1/TLR4/mTOR axis to reducing the expression of fibrosis and inflammatory cytokines in high glucose cultured rat mesangial cells. Exp Clin Endocrinol Diabetes 127:630–640
Wu C, Wang Q, Lv C, Qin N, Lei S, Yuan Q, Wang G (2014) The changes of serum sKlotho and NGAL levels and their correlation in type 2 diabetes mellitus patients with different stages of urinary albumin. Diabetes Res Clin Pract 106:343–350
Liu YN, Zhou J, Li T, Wu J, Xie SH, Liu HF, Liu Z, Park TS, Wang Y, Liu WJ (2017) Sulodexide protects renal tubular epithelial cells from oxidative stress-induced injury via upregulating Klotho expression at an early stage of diabetic kidney disease. J Diabetes Res 2017:4989847
Navarro-Gonzalez JF, Sanchez-Nino MD, Donate-Correa J, Martin-Nunez E, Ferri C, Perez-Delgado N, Gorriz JL, Martinez-Castelao A, Ortiz A, Mora-Fernandez C (2018) Effects of pentoxifylline on soluble Klotho concentrations and renal tubular cell expression in diabetic kidney disease. Diabetes Care 41:1817–1820
Yang XH, Zhang BL, Zhang XM, Tong JD, Gu YH, Guo LL, Jin HM (2020) EGCG attenuates renal damage via reversing Klotho hypermethylation in diabetic db/db mice and HK-2 cells. Oxidative Med Cell Longev 2020:6092715
Zhang XT, Wang G, Ye LF, Pu Y, Li RT, Liang J, Wang L, Lee KKH, Yang X (2020) Baicalin reversal of DNA hypermethylation-associated Klotho suppression ameliorates renal injury in type 1 diabetic mouse model. Cell Cycle 1–19. https://doi.org/10.1080/15384101.2020.1843815
Panah F, Ghorbanihaghjo A, Argani H, Asadi Zarmehri M, Nazari Soltan Ahmad S (2018) Ischemic acute kidney injury and klotho in renal transplantation. Clin Biochem 55:3–8
Castellano G, Intini A, Stasi A, Divella C, Gigante M, Pontrelli P, Franzin R, Accetturo M, Zito A, Fiorentino M et al (2016) Complement modulation of anti-aging factor Klotho in ischemia/reperfusion injury and delayed graft function. Am J Transplant 16:325–333
Soleymanian T, Ranjbar A, Alipour M, Ganji MR, Najafi I (2015) Impact of kidney transplantation on biomarkers of oxidative stress and inflammation. Iran J Kidney Dis 9:400–405
Donate-Correa J, Henriquez-Palop F, Martin-Nunez E, Perez-Delgado N, Muros-de-Fuentes M, Mora-Fernandez C, Navarro-Gonzalez JF (2016) Effect of paricalcitol on FGF-23 and Klotho in kidney transplant recipients. Transplantation 100:2432–2438
Van Beneden K, Mannaerts I, Pauwels M, Van den Branden C, van Grunsven LA (2013) HDAC inhibitors in experimental liver and kidney fibrosis. Fibrogenesis Tissue Repair 6:1
Chrun ES, Modolo F, Daniel FI (2017) Histone modifications: a review about the presence of this epigenetic phenomenon in carcinogenesis. Pathol Res Pract 213:1329–1339
McClure JJ, Li X, Chou CJ (2018) Advances and challenges of HDAC inhibitors in cancer therapeutics. Adv Cancer Res 138:183–211
Sato Y, Yanagita M (2018) Immune cells and inflammation in AKI to CKD progression. Am J Physiol Ren Physiol 315:F1501–F1512
Shi M, Flores B, Gillings N, Bian A, Cho HJ, Yan S, Liu Y, Levine B, Moe OW, Hu MC (2016) alphaKlotho mitigates progression of AKI to CKD through activation of autophagy. J Am Soc Nephrol 27:2331–2345
Lin W, Li Y, Chen F, Yin S, Liu Z, Cao W (2017) Klotho preservation via histone deacetylase inhibition attenuates chronic kidney disease-associated bone injury in mice. Sci Rep 7:46195
Lin W, Zhang Q, Liu L, Yin S, Liu Z, Cao W (2017) Klotho restoration via acetylation of peroxisome proliferation–activated receptor γ reduces the progression of chronic kidney disease. Kidney Int 92:669–679
Liu M, Li XC, Lu L, Cao Y, Sun RR, Chen S, Zhang PY (2014) Cardiovascular disease and its relationship with chronic kidney disease. Eur Rev Med Pharmacol Sci 18:2918–2926
Gao D, Zuo Z, Tian J, Ali Q, Lin Y, Lei H, Sun Z (2016) Activation of SIRT1 attenuates Klotho deficiency-induced arterial stiffness and hypertension by enhancing AMP-activated protein kinase activity. Hypertension 68:1191–1199
Zhang P, Li Y, Du Y, Li G, Wang L, Zhou F (2016) Resveratrol ameliorated vascular calcification by regulating Sirt-1 and Nrf2. Transplant Proc 48:3378–3386
Hsu SC, Huang SM, Chen A, Sun CY, Lin SH, Chen JS, Liu ST, Hsu YJ (2014) Resveratrol increases anti-aging Klotho gene expression via the activating transcription factor 3/c-Jun complex-mediated signaling pathway. Int J Biochem Cell Biol 53:361–371
Brilli LL, Swanhart LM, de Caestecker MP, Hukriede NA (2013) HDAC inhibitors in kidney development and disease. Pediatr Nephrol 28:1909–1921
Fontecha-Barriuso M, Martin-Sanchez D, Ruiz-Andres O, Poveda J, Sanchez-Nino MD, Valino-Rivas L, Ruiz-Ortega M, Ortiz A, Sanz AB (2018) Targeting epigenetic DNA and histone modifications to treat kidney disease. Nephrol Dial Transplant 33:1875–1886
Chun P (2017) Therapeutic effects of histone deacetylase inhibitors on kidney disease. Arch Pharm Res 41:162–183
Brilli LL, Swanhart LM, de Caestecker MP, Hukriede NA (2012) HDAC inhibitors in kidney development and disease. Pediatr Nephrol 28:1909–1921
Levine MH, Wang Z, Bhatti TR, Wang Y, Aufhauser DD, McNeal S, Liu Y, Cheraghlou S, Han R, Wang L et al (2015) Class-specific histone/protein deacetylase inhibition protects against renal ischemia reperfusion injury and fibrosis formation. Am J Transplant 15:965–973
Choi HS, Song JH, Kim IJ, Joo SY, Eom GH, Kim I, Cha H, Cho JM, Ma SK, Kim SW et al (2018) Histone deacetylase inhibitor, CG200745 attenuates renal fibrosis in obstructive kidney disease. Sci Rep 8:11546
Xiong C, Guan Y, Zhou X, Liu L, Zhuang MA, Zhang W, Zhang Y, Masucci MV, Bayliss G, Zhao TC et al (2019) Selective inhibition of class IIa histone deacetylases alleviates renal fibrosis. FASEB J 33:8249–8262
Pang M, Kothapally J, Mao H, Tolbert E, Ponnusamy M, Chin YE, Zhuang S (2009) Inhibition of histone deacetylase activity attenuates renal fibroblast activation and interstitial fibrosis in obstructive nephropathy. Am J Physiol-Renal Physiol 297:F996–F1005
Yang M, Chen G, Zhang X, Guo Y, Yu Y, Tian L, Chang S, Chen ZK (2019) Inhibition of class I HDACs attenuates renal interstitial fibrosis in a murine model. Pharmacol Res 142:192–204
Kang SW, Lee SM, Kim JY, Kim SY, Kim YH, Kim TH, Kang MS, Jang WH, Seo SK (2017) Therapeutic activity of the histone deacetylase inhibitor SB939 on renal fibrosis. Int Immunopharmacol 42:25–31
Na Liu SH, Ma L, Ponnusamy M, Tang J, Tolbert E, Bayliss G, Zhao TC, Yan H, Zhuang S (2013) Blocking the class I histone deacetylase ameliorates renal fibrosis and inhibits renal fibroblast activation via modulating TGF-beta and EGFR signaling. PLoS One 8:e54001
Zhang Y, Zou J, Tolbert E, Zhao TC, Bayliss G, Zhuang S (2020) Identification of histone deacetylase 8 as a novel therapeutic target for renal fibrosis. FASEB J 34:7295–7310
Lai L, Cheng P, Yan M, Gu Y, Xue J (2019) Aldosterone induces renal fibrosis by promoting HDAC1 expression, deacetylating H3K9 and inhibiting klotho transcription. Mol Med Rep 19:1803–1808
Chen F, Gao Q, Wei A, Chen X, Shi Y, Wang H, Cao W (2020) Histone deacetylase 3 aberration inhibits Klotho transcription and promotes renal fibrosis. Cell Death Differ. https://doi.org/10.1038/s41418-020-00631-9
Chung AC, Lan HY (2015) MicroRNAs in renal fibrosis. Front Physiol 6:50
Lu TX, Rothenberg ME (2018) MicroRNA. J Allergy Clin Immunol 141:1202–1207
Dey BK, Mueller AC, Dutta A (2014) Long non-coding RNAs as emerging regulators of differentiation, development, and disease. Transcription 5:e944014. https://doi.org/10.4161/21541272.2014.944014
Chen LL (2016) The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol 17:205–211
Abolghasemi M, Yousefi T, Maniati M, Qujeq D (2019) The interplay of Klotho with signaling pathway and microRNAs in cancers. J Cell Biochem 120:14306–14317
Morii K, Yamasaki S, Doi S, Irifuku T, Sasaki K, Doi T, Nakashima A, Arihiro K, Masaki T (2019) microRNA-200c regulates KLOTHO expression in human kidney cells under oxidative stress. PLoS One 14:e0218468
Mehi SJ, Maltare A, Abraham CR, King GD (2014) MicroRNA-339 and microRNA-556 regulate Klotho expression in vitro. Age (Dordr) 36:141–149
Liu Y, Lai P, Deng J, Hao Q, Li X, Yang M, Wang H, Dong B (2019) Micro-RNA335-5p targeted inhibition of sKlotho and promoted oxidative stress-mediated aging of endothelial cells. Biomark Med 13:457–466
Rodrigues CE, Capcha JMC, de Bragança AC, Sanches TR, Gouveia PQ, de Oliveira PAF, Malheiros DMAC, Volpini RA, Santinho MAR, Santana BAA et al. (2017) Human umbilical cord-derived mesenchymal stromal cells protect against premature renal senescence resulting from oxidative stress in rats with acute kidney injury. Stem Cell Res Ther 8. https://doi.org/10.1186/s13287-017-0475-8
Liang H, Yang K, Xin M, Liu X, Zhao L, Liu B, Wang J (2017) MiR-130a protects against lipopolysaccharide-induced glomerular cell injury by upregulation of Klotho. Pharmazie 72:468–474
Grange C, Papadimitriou E, Dimuccio V, Pastorino C, Molina J, O'Kelly R, Niedernhofer LJ, Robbins PD, Camussi G, Bussolati B (2020) Urinary extracellular vesicles carrying klotho improve the recovery of renal function in an acute tubular injury model. Mol Ther 28:490–502
Shilo V, Mor-Yosef Levi I, Abel R, Mihailović A, Wasserman G, Naveh-Many T, Ben-Dov IZ (2017) Let-7 and microRNA-148 regulate parathyroid hormone levels in secondary hyperparathyroidism. J Am Soc Nephrol 28:2353–2363
Liu Y, Bi X, Xiong J, Han W, Xiao T, Xu X, Yang K, Liu C, Jiang W, He T et al (2019) MicroRNA-34a promotes renal fibrosis by downregulation of Klotho in tubular epithelial cells. Mol Ther 27:1051–1065
Wu C, Lv C, Chen F, Ma X, Shao Y, Wang Q (2015) The function of miR-199a-5p/Klotho regulating TLR4/NF-kappaB p65/NGAL pathways in rat mesangial cells cultured with high glucose and the mechanism. Mol Cell Endocrinol 417:84–93
Jia Y, Zheng Z, Xue M, Zhang S, Hu F, Li Y, Yang Y, Zou M, Li S, Wang L et al (2019) Extracellular vesicles from albumin-induced tubular epithelial cells promote the M1 macrophage phenotype by targeting Klotho. Mol Ther 27:1452–1466
Kang WL, Xu GS (2016) Atrasentan increased the expression of klotho by mediating miR-199b-5p and prevented renal tubular injury in diabetic nephropathy. Sci Rep 6:19979
Ye H, Su B, Ni H, Li L, Chen X, You X, Zhang H (2018) microRNA-199a may be involved in the pathogenesis of lupus nephritis via modulating the activation of NF-kappaB by targeting Klotho. Mol Immunol 103:235–242
Shilo V, Ben-Dov IZ, Nechama M, Silver J, Naveh-Many T (2015) Parathyroid-specific deletion of dicer-dependent microRNAs abrogates the response of the parathyroid to acute and chronic hypocalcemia and uremia. FASEB J 29:3964–3976
Lv W, Fan F, Wang Y, Gonzalez-Fernandez E, Wang C, Yang L, Booz GW, Roman RJ (2018) Therapeutic potential of microRNAs for the treatment of renal fibrosis and CKD. Physiol Genomics 50:20–34
Butz H, Racz K, Hunyady L, Patocs A (2012) Crosstalk between TGF-beta signaling and the microRNA machinery. Trends Pharmacol Sci 33:382–393
Almaani S, Meara A, Rovin BH (2017) Update on lupus nephritis. Clin J Am Soc Nephrol 12:825–835
Yung S, Yap DY, Chan TM (2017) Recent advances in the understanding of renal inflammation and fibrosis in lupus nephritis. F1000Res 6:874
Cen H, Zhou M, Leng RX, Wang W, Feng CC, Li BZ, Zhu Y, Yang XK, Yang M, Zhai Y et al (2013) Genetic interaction between genes involved in NF-kappaB signaling pathway in systemic lupus erythematosus. Mol Immunol 56:643–648
Jiang T, Tian F, Zheng H, Whitman SA, Lin Y, Zhang Z, Zhang N, Zhang DD (2014) Nrf2 suppresses lupus nephritis through inhibition of oxidative injury and the NF-kappaB-mediated inflammatory response. Kidney Int 85:333–343
Rupaimoole R, Slack FJ (2017) MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 16:203–222
Chen J, Ning Y, Zhang H, Song N, Gu Y, Shi Y, Cai J, Ding X, Zhang X (2019) METTL14-dependent m6A regulates vascular calcification induced by indoxyl sulfate. Life Sci 239:117034
Liu L, Zou J, Guan Y, Zhang Y, Zhang W, Zhou X, Xiong C, Tolbert E, Zhao TC, Bayliss G, Zhuang S (2019) Blocking the histone lysine 79 methyltransferase DOT1L alleviates renal fibrosis through inhibition of renal fibroblast activation and epithelial-mesenchymal transition. FASEB J 33:11941–11958
Han X, Sun Z (2020) Epigenetic regulation of KL (Klotho) via H3K27me3 (histone 3 lysine [K] 27 trimethylation) in renal tubule cells. Hypertension 75:1233–1241
Li Y, Ren D, Xu G (2019) Long noncoding RNA MALAT1 mediates high glucose-induced glomerular endothelial cell injury by epigenetically inhibiting klotho via methyltransferase G9a. IUBMB Life 71:873–881
Shah RR (2019) Safety and tolerability of histone deacetylase (HDAC) inhibitors in oncology. Drug Saf 42:235–245
Filì C, Candoni A, Zannier ME, Olivieri J, Imbergamo S, Caizzi M, Nadali G, Di Bona E, Ermacora A, Gottardi M et al (2019) Efficacy and toxicity of decitabine in patients with acute myeloid leukemia (AML): a multicenter real-world experience. Leuk Res 76:33–38
Stancheva TCaI (2008) Methyl-CpG binding proteins: specialized transcriptional repressors or structural components of chromatin? Cell Mol Life Sci 65:1509–1522
Acknowledgments
We thank former and current laboratory members Lin Liu, Qin Zhang, Wenjun Lin, Shasha Yin, Dawei Cai, Fangfang Bi, Yanning Li, Fang Chen, Ai Wei, Qi Gao, Xiaobo Zhu, Xingren Chen, and Lijun Zhang for their contributions to the publications substantiating this article.
Funding
This work is supported by research grants from National Nature Science Foundation of China General Program 81970577 and 81670762 to W.C.
Author information
Authors and Affiliations
Contributions
J.X. searched the literatures drafted the manuscript. W.C. reviewed, edited, and wrote the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Xia, J., Cao, W. Epigenetic modifications of Klotho expression in kidney diseases. J Mol Med 99, 581–592 (2021). https://doi.org/10.1007/s00109-021-02044-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-021-02044-8